The connective tissue of vascular walls is formed from two principal types of protein. Collagen, in general, the principal proteinaceous component of connective tissue, constitutes the structural element imparting strength to the tissue. However, where the demand for elasticity is great as in the aortic arch and descending thoracic aorta, there is twice as much elastin as collagen. In the vascular wall, and particularly in the internal elastic lamina thereof, collagen is associated with natural elastic fibers formed from a different type of protein, known as tropoelastin. In the relaxed vascular wall, collagen fibers tend to be folded or crimped, and the elastic fibers are in a retracted state. Upon distention or stretching, the elastic fibers become stretched, and, before their extension limit is approached, the collagen fibers come into tension to bear the load. As the load diminishes, the elastic fibers draw the wall back to its original dimension and the collagen fibers back into a folded state.
The above can also be demonstrated experimentally, for if the collagen component of an intact ligament is removed in vitro by the enzyme collagenase, the resultant stress-strain relationship clearly indicates that the elastic component, elastin, is principally responsible for the initial high yield response of the intact ligament. Conversely, removal of elastin by the enzyme elastase leaves collagen which is observed to be responsible for only the final portion of the response of the intact ligament. See Introductory Biophysics, F. R. Hallett et al. (Halsted Press, 1977).
Presently available synthetic vascular materials, such as Dacron, are quite different from natural connective tissue in that the synthetic weave can be viewed as providing the structural analog of folded collagen, but there is no true elastomeric component therein.
The central portion of the elastic fibers of vascular wall, skin, lung and ligament is derived from a single protein called tropoelastin. Elastin, the actual elastomeric component of biological elastic fibers, is composed of a single protein and is formed from the cross-linking of the lysine residues of tropoelastin. The sequence of elastin can be described as a serial alignment of alanine-rich, lysine containing cross-linking sequences alternating with glycine-rich hydrophobic sequences. More than 80% of the elastin sequence is known, and it has been shown that vascular wall tropoelastin contains a repeat hexapeptide (Ala-Pro-Gly-Val-Gly-Val).sub.n, a repeat pentapeptide (Val-Pro-Gly-Val-Gly).sub.n, and a repeat tetrapeptide (Val-Pro-Gly-Gly).sub.n where Ala, Pro, Val and Gly, respectively, represent alanine, proline, valine, and glycine amino acid residues. These residues can also be represented, respectively, as A, P, V and G, inasmuch as amino acids can be referred to either by standard three-letter or one-letter abbreviations. See, for example, Organic Chemistry of Biological Compounds, pages 56-58 (Prentice-Hall, 1971). Further, in this application, all peptide representations conform to the standard practice of writing the NH.sub.2 -terminal amino acid residue on the left of the formula and the CO.sub.2 H-terminal amino acid residue on the right. Furthermore, unless otherwise specified all amino acids are of the L-configuration, with the exception of glycine, which is optically inactive.
The nature of the amino acid sequence in the vicinity of the tropoelastin cross-links is also known. Moreover, a high polymer of the hexapeptide has been synthesized, and found to form cellophane-like sheets. In view of this, and its irreversible association on raising the temperature in water, the hexapeptide is, therefore, thought to provide a structural role in the natural material. On the other hand, synthetic high polymers of the pentapeptide and of the tetrapeptide have been found to be elastomeric when cross-linked and have the potential to contribute to the functional role of the elastic fiber. In fact, the chemically cross-linked polypentapeptide can, depending upon its water content and degree of crosslinking, exhibit the same elastic modulus as native aortic elastin.
More recently, a synthetic polypentapeptide based on the pentapeptide sequence disclosed above was disclosed and claimed in U.S. Pat. No. 4,187,852 to Urry and Okamoto. Furthermore, a composite bioelastic material based on an elastic polypentapeptide or polytetrapeptide and a strength-giving fiber was disclosed and claimed in U.S. Pat. No. 4,474,851 to Urry. Additionally, a bioelastic material having an increased modulus of elasticity formed by replacing the third amino acid in a polypentapeptide with an amino acid of opposite chirality was disclosed and claimed in U.S. Pat. No. 4,500,700 to Urry and to an enzymatically cross-linked polypeptide as disclosed in and claimed in U.S. Pat. No. 4,589,882. Furthermore, U.S. Pat. No. 4,605,413 is directed to a chemotactic peptide, while Ser. No. 793,225, directed to a second chemotactic peptide is pending. Also pending is Ser. No. 853,212, directed to a segmented polypeptide bioelastomer for the modulation of elastic modulus.
Also pending is Ser. No. 900,895 which describes the temperature correlated force and structure development of various elastomeric polytetrapeptides and polypentapeptides. In that application, the present inventors disclosed that the above polypeptides exhibit elastomeric force development which can be varied as a function of temperature. In particular, the present inventors found that by varying the structure of the repeating tetrameric or pentameric unit of the polypeptide that it is possible to effect the range of temperature over which the elastomer develops elastomeric force.
However although the development of elastomeric force for these polypeptides can now be induced as a function of temperature, it would be extremely desirable to be able to effect the development of elastomeric force without resorting to altering the temperature of the system. It would also be extremely desirable to be able to effect the development of elastomeric force in a highly controllable and reversible manner.